hereditary nonpolyposis colorectal cancer and cancer...

Review ArticleHereditary Nonpolyposis Colorectal Cancer and CancerSyndromes Recent Basic and Clinical Discoveries

Erbao Chen Xiaojing Xu and Tianshu Liu

Department of Medical Oncology Zhongshan Hospital Fudan University Shanghai China

Correspondence should be addressed to Tianshu Liu liu tianshu99163com

Received 19 December 2017 Revised 12 March 2018 Accepted 20 March 2018 Published 23 April 2018

Academic Editor Akira Hara

Copyright copy 2018 Erbao Chen et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Approximately one-third of individuals diagnosed with colorectal cancer have a family history of cancer suggesting that CRCsmay result from a heritable component Despite the availability of current gene-identification techniques only 5 of all CRCsemerge from well-identifiable inherited causes for predisposition including polyposis and nonpolyposis syndromes Hereditarynonpolyposis colorectal cancer represents a large proportion of cases and robustly affected patients are at increased risk forearly onset synchronous andmetachronous colorectal malignancies and extracolonic malignancies HNPCC encompasses severalcancer syndromes such as Lynch syndrome Lynch-like syndrome and familial colorectal cancer type X which have remarkableclinical presentations and overlapping genetic profiles that make clinical diagnosis a challenging task Therefore distinguishingbetween the HNPCC disorders is crucial for physicians as an approach to tailor different recommendations for patients and theirat-risk family members according to the risks for colonic and extracolonic cancer associated with each syndrome Identification ofthese potential patients through epidemiological characteristics and new genetic testing can estimate the individual risk whichinforms appropriate cancer screening surveillance andor treatment strategies In the past three years many appealing andimportant advances have been made in our understanding of the relationship between HNPCC and CRC-associated syndromesThe knowledge from the genetic profile of cancer syndromes and unique genotype-phenotype profiles in the different syndromeshas changed our cognition Therefore this review presents and discusses HNPCC and several common nonpolyposis syndromeswith respect to molecular phenotype histopathologic features and clinical presentation

1 Introduction

Colorectal cancers (CRCs) are one of the most commonmalignancies and represent the third most common cancerin men and the second in women worldwide It is estimatedthat one-third of individuals diagnosedwith colorectal cancerhave a family history of cancer [1] However approximately5 to 10 of all CRCs called hereditary CRCs are relatedto mutations and defects in certain genes [2] In additionapproximately 20ndash30 of familial CRC patients have at leastone relative affected by neoplasms that act as nonsyndromicfamilial CRCs and are likely driven by shared genes andorenvironmental factors [3 4] In individuals high-risk hered-itary predisposition syndromes have been associated witha 70ndash100 lifetime risk for earlier development of CRCsor metachronous cancers and many syndromes carry anincreased risk for extra-intestinal manifestations [5]

The hereditary CRCs syndromes are broadly divided intononpolyposis and polyposis syndromes In 1966 Lynch firstdefined familial CRC type I for families with CRC only andtype II for families with both CRC and gynecological cancer[6] Later the term hereditary nonpolyposis colorectal cancer(HNPCC) was recommended to emphasize the absence ofa polyposis phenotype Currently HNPCC defines a patientwho meets Amsterdam criteria I or II [7ndash9] and HNPCCpatents are prone to develop synchronous and metachronouscancers at relative young ages Generally the ldquononpolyposisrdquolabel of HNPCC can be misleading and confusing to physi-cians because adenomas typically present a villous growthcharacteristic and have different degrees of cell dysplasia [10]Therefore identification of these individuals is critical forearly intervention and treatment of associated malignanciesto reduce HNPCC-associated morbidity and mortality Mostof the cancer syndromes involve inheritedmutations in genes

HindawiJournal of OncologyVolume 2018 Article ID 3979135 11 pageshttpsdoiorg10115520183979135

2 Journal of Oncology

HNPCC clinically determined

MMR-deficient

MMR-proficient

Lynch syndromeGermline mutation+Extracolonic cancers

Lynch-like syndromeGermline mutationminus

Rare extracolonic cancersRelatively younger age

FCCXUnknown genetic causesNo extracolonic cancers

Figure 1 The category of hereditary nonpolyposis colorectal cancer

that modulate growth processes in colonic stem cells andorprotect the fidelity of the genome passed into progeny cellsGiven the substantial risk of synchronous and metachronouscancer these mutation carriers are recommended to abideby standard surveillance and comprehensive managementprotocols when compared with the general population withan average CRC risk profile The role of genetic counselingbecomes crucial in treating these patients

As such understanding and distinguishing the vari-ous syndromes are useful and clinically meaningful as theapproach to diagnosing and surveilling patients and their at-risk family members Previously testing of patient tumorsfor microsatellite instability (MSI) and mutation of DNAMMR genes is an effective strategy to discriminate patientsat risk for Lynch syndrome Cancer-free individuals whosefamily history indicates suspicion for a hereditary cancersyndrome should undertake clinical genetic evaluation andreceive genetic counseling Even if a mutation is not detectedpeople may benefit from the genetic evaluation in otherinterventions to reduce future cancer risk

This paper provides a comprehensive literature reviewon the most common HNPCC and HNPCC-associatedcancer syndromes (including Lynch syndrome Lynch-likesyndrome and familial colorectal cancer type X) that presentdistinguishing molecular phenotypes histopathologic fea-tures and clinical presentations among different subtypes(Figure 1)

2 Diagnosis of Hereditary NonpolyposisColorectal Cancer

The Amsterdam I clinical criteria for HNPCC which focuson the number and ages of family members with colorectalcancer were published in 1990 to standardize the inclusioncriteria for clinical research studies [9] For kindred familiesfulfilling the Amsterdam criteria the chance of identifyinga germline mutation is 40 to 50 [11] Similarly 40 ofpatients with an identified geneticmutation fail tomeet Ams-terdam criteria [12] Therefore Amsterdam I criteria werebelieved to be insufficiently sensitive and to be missing clearfamilial clustering of extracolonic malignancies which led toestablishment of the Amsterdam II criteria in 1999 which

improved the diagnostic sensitivity and included associatedcancers (eg endometrial small bowel) Later Bethesdacriteria were created and revised in 2004 to identify CRCpatients who should undergo pathologic examination (MSIandor immunohistochemistry (IHC) assessment for theMMR protein deficiency in the tumor) for HNPCCLynchsyndrome [13] (Box 1)

Regardless the Amsterdam criteria fail to identifyapproximately 50 of cases and Bethesda guidelines fail toidentify at least 30 of cases [14] which has led to increasedsupport for the universal application of the polymerasechain reaction (for detection of MSI-high tumors) andorIHC testing to all CRC specimens [15] Currently manyguidelines suggest two possible approaches to screen outLynch syndrome a universal one that is to test every patientwith CRC and a selective one (Jerusalem guidelines) whichbroadens the indications for MSI or IHC testing to everyindividual with CRC diagnosed prior to age 70 plus patientsdiagnosed at older ages who meet the Bethesda criteria [16]with the latter approach missing more than a quarter ofpatients with Lynch syndrome (Figure 2) This justificationalso supports the universal testing for endometrial cancer[17] Universal testing followed by germline testing offersthe highest sensitivity (and somewhat lower specificity)than alternative screening strategies although the increasein the diagnostic yield is modest compared with criteria-based screening techniques [18] Cost-effectiveness analysesdemonstrate varying results [19 20] In this review HNPCCgenerally refers to any family that meets the Amsterdam IIIor Revised Bethesda guidelines

3 Lynch Syndrome

31 Overview One of the first hereditary nonpolyposis can-cer-associated syndromes to be identified Lynch syndromeis also the most relevant to HNPCC It is estimated thatLS accounts for approximately 3 of all CRC cases and itsprevalence in the general population is one in 440 [21] Lynchsyndrome also increases the risk for extracolonic cancerssuch as that of the endometrium (50ndash60) ovaries (9ndash14)stomach (13ndash19) small intestine urinary tract and centralnervous system [22 23] (Table 1) Lynch syndrome is now

Journal of Oncology 3

CRC lt 70 or CRC gt 70 and revisedBethesda guidelinesAmsterdam I or II

Abnormal (loss ofprotein expression plusmn MSI

IHC plusmn MSI based ontumor

Normal (IHC and non-MSI)

Loss of MLH1 Loss of MSH2 MSH6 or PMS2FCCX

Positive

Positive

Negative

Negative Germline testing of the corresponding gene

Sporadic CRC Lynch syndrome Lynch-like syndrome

Somatic BRAF mutation plusmn MLH1 promoter methylation analysis

Figure 2 The diagnostic algorithm for HNPCC-associated cancer syndrome

Amsterdam criteria I(1) At least three relatives with CRC(2) One of which is a first-degree relative of the other two(3) Colorectal cancer affecting at least two successive generations(4) At least one patient with colorectal cancer diagnosed lt50 years(5) Familial adenomatous polyposis should be excluded(6) Tumors should be verified by pathologic examinationAmsterdam criteria II(1) There should be at least three relatives with an HNPCC-associated cancer (CRC cancer of the

endometrium small bowel ureter or renal pelvis)(2) One patient must be a first-degree relative of the other two(3) Colorectal cancer affecting at least two successive generations(4) As least one patient should be diagnosed lt50 year(5) Familial adenomatous polyposis should be excluded(6) Tumors should be verified by pathologic examinationRevised Bethesda criteria(1) CRC diagnosed in one patient lt50 years(2) Presence of synchronous or metachronous colorectal or other HNPCC-associated tumors(3) Pathologic features of a microsatellite instability-high cancer diagnosed in a patient lt60 years(4) CRC diagnosed in a patient with at least one first-degree relatives with an HNPCC-related

tumor with one of the cancer diagnosed lt50 years (including adenoma lt40 years)(5) CRC diagnosed in a patient with at least two first-or second-degree relatives with HNPCC-

related tumors

Box 1 HNPCC clinical diagnostic criteria

well established as an inherited autosomal dominant predis-position to CRC and certain extracolonic cancers are derivedfrom defective DNA mismatch repair (MMR) genes whichare a system for maintaining genome integrity Accumulatinggenetic mutations of MMR genes lead to tracts of repetitiveDNA sequences called microsatellites which typically mani-festmicrosatellite instability (MSI) [24]MSI facilitates tumorcell proliferation invasion andmetastasis through activatingoncogenes or suppressing tumor suppressors [25] and allowsdetection of microsatellite instability (MSI) during tumorprogression [26]

32TheMolecular Phenotype of Lynch Syndrome Lynch syn-drome is an autosomal dominant condition caused by amalfunctioningMMR system resulting from the pathologicalmutation in at least one of the MMR genes Germlinetesting for germline mutations in the MMR genesmdashmutShomologue 2 (MSH2) mutL homologue (MLH1) mutShomologue 6 (MSH6) and postmeiotic segregation increased2 (PMS2)mdashcan discriminate Lynch syndrome from Lynchkindreds During cellular proliferation and differentiationDNA randomly produces errors that may include singlebase mismatch insertions misincorporation and deletion of


Table 1 Genes associated and cancer risks for HNPCC

Syndrome Gene Percentagesyndrome Cancer risks 95 CILynch syndrome MLH1 60 Colorectum 52 (31ndash90)

Endometrium 21 (9ndash82)Stomach 11ndash19Ovary 38 (3ndash81)

Hepatobiliary 2ndash7Upper urinary tract 4-5

Pancreas 3-4Small bowel 1ndash4Glioblastoma 1ndash3

Lynch syndrome MSH2 20 Colorectum 49 (29ndash85)Lynch syndrome MSH6 6 Colorectum 18 (13ndash30)

Endometrium 17 (8ndash47)Stomach le3Ovary 1 (0-1)

Urinary tract lt1Lynch syndrome PMS2 12 Colorectum 15ndash20

Endometrium 15Lynch syndrome EPCAM lt3 Endometrium 57 (22ndash82)

Stomach 11ndash19Ovary 20 (1ndash66)


Pancreas 3-4Glioblastoma 1ndash3

bases The function of the MMR gene system is to recognizeand maintain the fidelity of DNA by correcting the structureof DNA replication errors [27] Approximately 70ndash90 ofLynch syndrome tumors have germline MLH1 or MSH2mutations MLH1 and MSH2 mutations confer an elevatedlifetime cancer risk when compared to MSH6 and PMS2[28 29] MSH6 and PMS2 are detected in the remainingapproximately 10ndash20 of LS cases and up to 3 of LS iscaused by deleterious mutations in epithelial cell adhesionmolecule (EPACM) The deletion of the 31015840 end of EPCAMimmediately upstream of MSH2 on chromosome 2 whichcauses allele-specific methylation of the MSH2 promoter isa relatively rare cause for epigenetic silencing of MSH2 [30]Somatic BRAF mutations can be useful to rule out Lynchsyndrome because they frequently occur in sporadic MSICRCs caused by MLH1 promoter methylation BRAF andpromoter methylation are usually conducted in patients witha lack of MLH1 protein to eliminate the possibility of Lynchsyndrome

Recent studies have focused on exploring the novelsomatic mutations in the Lynch syndrome For instanceRNF43 one of the E3 ubiquitin ligases acts as a negative-regulatory factor of the WNT pathway via reducing mem-brane surface expression [31] RNF43 had been regarded as apivotal mutational target of microsatellite instability (MSI) in70ndash80 of sporadic colorectal carcinogenesis [32] SimilarlyRNF43 mutations occurred in approximately 40 of LS-CRCs which was significantly lower than the percentage

occurring in sporadic colorectal cancers [33] Additionalsomatic mutations of POLE and MSH3 identified in LS-CRCs are regarded to further accumulate somatic mutationsduring tumor progression [34] Constitutional MMR defi-ciency (CMMRD) a very rare subtype of MMR deficiency isa distinct childhood cancer predisposition syndrome charac-terizedcaused by the presence of MMR homozygous muta-tions or inherited biallelic MMR protein inactivation [35]The CMMRD harbors more somatic mutations comparedwith Lynch syndrome individuals especially in the DNA-binding domain of the TP53 gene Some novel mutationssuch as POLE and POLD1 have also been identified in theCMMRD [36] Female POLD1 mutation carriers have a highrisk of endometrial cancer and a moderate risk of breastcancer [37] (Table 2)

33 The Histopathologic Features and Clinical Presentation ofLynch Syndrome Since Lynch syndromehas been extensivelycharacterized however the incidence of Lynch syndromevaries by the endemicity of all diagnosed CRC patients indifferent populations Similar to the case of European indi-viduals with Lynch syndrome [38] recent clinic-based obser-vations have reported deleterious mutations that disrupt thefunction of the MMR gene product (MLH1 (61) MSH2(21) PMS2 (12) andMSH6 (6)) in anAfricanAmericanpopulation with Lynch syndrome [39] The percentage ofMMR gene mutations in the tumors was approximately13 in Latino individuals which is similar to estimates in


Table 2 Germline and somatic genetic and epigenetic characteristics of HNPCC-associated cancer syndrome

Lynch syndrome Lynch-like syndrome FCCXTumor MMR MSI MSI MSS

Germline mutation MSH2 MLH1 MSH6 PMS2EPCAM ERBB2 MCM9 RPS20 SEMA4A

Somatic mutation Second allele of MMR Both alleles of a MMR RASSF9 NTS SETD6 NDUFA9AXIN2 MYC H2AFZ

Epigenetic phenotype MSH2 promoter methylation None RASL10BMSS microsatellite stable MSI microsatellite instability FCCX familial colorectal cancer X MMR mismatch repair

non-Hispanicwhite individuals Furthermore approximately619 of deficient MMR tumors were indeed attributableto germline MMR gene mutations by in-depth molecularanalysis and Latino patients with Lynch syndrome developcancer at a younger age and have a higher percentage ofrectal cancers and advanced disease which is consistentwith observations in other studies [40] The incidence ofLynch syndrome among diagnosed CRC patients in Japan is07 which is slightly lower than that reported previouslybut within the same range (07ndash37) as that in recentinvestigations [41] The CRC incidence in Finnish MLH1mutation carrierswas lower than that in non-Finnish carriersbut not significantly [42]

Very few studies have compared the epidemiologicalcharacteristics and clinicopathological differences betweenLynch syndrome patients with other disease and those withLynch syndrome only TheMSH6 and PMS2 mutations indi-cate a decreased risk of cancer incidencewhen comparedwithMLH1 and MSH2 mutations [28] however when comparingindividuals with breast cancer only to those with CRC onlyMSH6 and PMS2 mutations were more frequent than MLH1and MSH2 mutations [43] Inflammatory bowel disease(IBD) is associated with a 17-fold greater CRC risk (95confidence interval 12ndash22) due to inflammatory factors[44] In patients with both Lynch syndrome and IBD thereis an increased CRC risk at a younger onset compared tothose with Lynch syndrome only especially in patients withulcerative colitis [45 46]

Screening by colonoscopy enables the early detection andremoval of preinvasive neoplasia or adenomas before thepresence of symptoms and is the main strategy of secondaryprevention in Lynch syndrome patients [47 48] Althoughthe removal of adenomas is regarded as an effective way toprevent CRC and death CRC still occurs frequently How-ever the overall survival is good for patientswithCRCand forpatients with first endometrial and ovarian cancer [49] Theoutcomes for Lynch syndrome patients who have surviveda first cancer attack are of great interest In patients whohave their first cancer before the age of 40 the cumulativeincidences for any subsequent cancer are high specifically73 for MLH1 mutations 76 for MSH2 mutations and52 forMSH6mutations [50] Of note the relative incidenceof subsequent cancer compared with the incidence of firstcancer is slightly but insignificantly higher than the cancerincidence in patients with Lynch syndrome without previouscancer MSH2 mutation patients tend to have prostate andurinary tract cancers Upper gastrointestinal tract cancers

frequently occur inMLH1mutation carriers whereas ovariancancer occurs mainly in younger women which is contraryto ovarian cancers in BRCA12 mutation carriers and in thegeneral population [51]

For treatment MSI in a tumor usually causes frameshiftmutations in the DNA resulting in immunogenic neoanti-gens that induce an immune reaction against the tumorThe approval of pembrolizumab use for solid tumors withhigh-level microsatellite instability or mismatch repair defi-ciency by the US Food and Drug Administration highlightsthe promise of precision immuno-oncology Immunother-apy strategies are based on immunopathology Hencepatients would benefit from tumor immunopathology espe-cially for some immune checkpoints such as PD1 (pro-grammed cell death 1) and PDL1 (programmed cell death 1ligand 1)

4 Lynch-Like Syndrome

41 Overview As many as 60ndash70 patients who fulfill theAC criteria in the clinical and MMR deficiency in the tumorbut for whom germline testing lacks a detectable germlinemutation are defined as having ldquoLynch-like syndromerdquo [52]Due to an early-onset age and abnormal MMR proteinsimilar to those of Lynch syndrome patients Lynch-likesyndrome patients are nearly impossible to differentiate fromLynch syndrome patients They all manifest MSI within theircancers and immunohistochemistry detects abnormal DNAMMR proteinmdashnot only for MLH1 but also for the mainDNA MMR proteins including MSH2 MSH6 and PMS2as with true Lynch syndrome cancers [53] AdditionallyLynch-like syndrome patients have a slightly higher butinsignificant mean age of onset than that of Lynch syn-drome patients (537 versus 485 years of onset) The onlydifferentiating clinicopathological features between these twocancer syndromes are as follows (1) The majority of thosewith Lynch-like syndrome tend to have CRC in the rightcolon (93) when compared to those with Lynch syndrome(45) [54] (2) Epidemiologic studies to date have describedlower standardized incidence ratios for colorectal cancer(212 versus 604) and noncolorectal cancer Lynch syndrome-associated cancers (169 versus 281) in Lynch-like syndromecompared with Lynch syndrome Lynch-like syndrome isestimated to account for as many as 70 of clinical Lynchsyndrome patients suspected to have a high MSI conditionand the absence of MMR proteins Consequently cliniciansare limited in their knowledge of the genetic diagnosis of


these patients and are unconfident regardingwhich screeningshould be recommended [55]

42 The Molecular Phenotype of Lynch-Like Syndrome Themechanism between Lynch syndrome and Lynch-like syn-drome for causing the generation of MSI within Lynch-likesyndrome patients is appealing and elusiveThree hypotheseshave been proposed to explain why Lynch-like syndromepatients showMSI in the tumors but noDNAMMRgermlinemutation (1) there exist unknown gene mutations other thanthe DNA MMR genes in the germline that can drive MSILynch syndrome and Lynch-like syndrome CRC frequentlyharbor not only activating ERBB2 mutations but also specificmutational patterns in PIK3CA and KRAS FurthermoreERBB2-mutated MSI CRC is susceptible to irreversible pan-HER blockade [56] Recently MCM9 was identified as theDNA helicase in the MMR complex and loss of helicaseactivity results in MSI MCM9 recruitment and loadinginto chromatin are MSH2-dependent and strengthens therecruitment of MLH1 to chromatin binding sites and cellslacking the MMR protein lose the maintenance of genomestability [57] Liu et al reported that MCM9 unknown sig-nificance variants were only observed in a small proportionof Lynch-like syndrome patients and that MCM9 mutationsare unable to explain the MSI in most Lynch-like syndromecases [58] (2) Limited methods failed to detect germlinemutations in the DNA MMR genes [59] A new method ofallelic dropout in long PCR was performed to seek potentialregions of rearrangement in the MSH2 gene Six of 10(60) patients with previously unexplained MSH2-deficientLynch syndrome were detected as harboring an inversionalteration from exon 1 to 7 in theMSH2 gene [60] Traditionalgermline testing screens exons and splice sites for deleteriousmutations but does not review introns or RNA transcriptsfor harmful alterations cDNA screening to identify patientssuspected to have cryptic MMR gene rearrangements is rec-ommended [61] (3) An unrevealed biological process withinthe tumors not involving a germline mutation for instancea double somatic mutation in the MMR gene mostly occursin sporadic CRCs [62] For instance approximately 60 ofLynch-like CRCs manifest biallelic somatic inactivation ofMMR genes within the tumor A somatic mutation in oneallele of anMMRgene alongwith loss of heterozygosity of theother allele is the most commonly described pattern Thesesomatic MMR gene mutations are likely sporadic eventssuggesting that such tumors are most likely cancers withsporadic DNA MMR deficiency Somatic mutation of POLEwas identified as a rare possibly underlying cause for MMRdeficiency in Lynch-like syndrome [63]

Other possible causes of Lynch-like syndrome-associatedcancers could include false-positive results showing MSIEach of these possibilities may be part of the reason forLynch-like syndrome because they are not mechanisms thatconflict with each other and given the standardized inci-dence ratios of Lynch-like syndrome between the ratios forLynch syndrome and sporadic colorectal cancer Lynch-likesyndrome may be a heterogeneous condition between thesetwo extremes In exploring the three hypotheses the firstregarding an unknown germline gene drivingMSI is themost

remote The DNA MMR apparatus is well studied and mostassociated components are known with no other reportsof germline mutations outside of these genes other thanEPCAM as described Mensenkamp et al made significantheadway in identifying that somatic mutations in MLH1and MSH2 are a frequent cause for inactivating DNA MMRfunction and subsequent MSI generation within Lynch-likesyndrome cancers [64]

43 The Histopathologic Features and Clinical Presentationof Lynch-Like Syndrome MUTYH encodes a base excisionrepair DNA glycosylase Mutations in this gene are found inMUTYH-associated polyposis (MAP) syndrome an autoso-mal inherited condition commonly featured by the presenceof a few to hundreds of colonic adenomatous polyps and anincreased CRC risk at a young age [65] Biallelic MUTYHmutations also account for a proportion of LLS cases [66]Patients with Lynch-like syndrome and Lynch syndromecaused by EPCAM deletion share common clinical featuresthat differ from patients with Lynch syndrome caused byMMR including a preference for the right colon a lowerdegree of fulfillment of the revised Bethesda guidelinesand an older mean age at CRC diagnosis [63] Patientswith Lynch-like syndrome more frequently have colorectalcarcinoma on the right side and are less likely to havesynchronous or metachronous carcinoma However thereare no significant differences in clinicopathological variablesbetween patients with Lynch-like syndrome and Lynch syn-drome with endometrial carcinoma [54]

5 Familial Colorectal Cancer Type X (FCCX)

51 Overview HNPCC is a clinically heterogeneous diseaseof which approximately 4 of cases are associated with Lynchsyndrome which may not conform to AC lt1 of cases arecorrelated to a Lynch-like syndrome and 2ndash4 of cases arediagnosed as FCCX [67] Familial colorectal cancer type X isa collective designation by Lindor [68] and refers to familieswho fulfill AC I but exhibit no evidence of a deficient DNAMMR gene (no deleterious germline mutations in the MMRgenes nomicrosatellite instability or no absence of immune-histochemical staining ofMMR protein) wherein ldquoXrdquo is usedto describe the unknown nature of the etiology As is thecase for other familial cancer syndromes the identification ofthe genes associated with FCCX will facilitate the moleculardiagnosis of the disease and the development of appropriatesurveillance guidelines and clinical management protocolsfor these patients

52 The Molecular Phenotype of FCCX The genomic pro-files of FCCX cancers show similarities to sporadicMMR-proficient CRC since the clinical performance andhistopathological features resemble sporadic CRC Chro-mosomal instability (CIN) is a type of genomic instability asa result the chromosomal structures are unstable and hencefacilitate carcinogenesis Recently high-resolution genomicprofiling elaborated a CIN-like profile that discriminated65 of colorectal cancers associated with FCCX from LSbased on the gain of chromosomal region 20q and loss of


18 [69] The genomic profiles of FCCX cancers are verysimilar to those of stable early tumors but highly differentfrom that of LS Genome-wide linkage analysis suggests thatlinkage at four chromosomal regions 2p243 4q131 4q3121and 12q212ndashq2131 are responsible for FCCX cancers andRASSF9 and NTS are considered good candidates becauseof their possible involvement in colorectal epitheliumcarcinogenesis [70] Except for the linkage to certainchromosomal regions genomic insertiondeletion (INDEL)and copy number variation (CNV) also locate parts or theentire sequences of genes and hence may regulate geneexpression or function [71] Some mutations in severalcancer-related genes such as BMPR1a are also detected inFCCX but an independent cohort of 22 probands fromFCCX families have revealed that BMPR1a mutations are nota major contributor of FCCX incidence [72]

Moreover previous studies suggest that mutations of theGALNT12 gene might elucidate the unknown etiology offamilial CRC However investigators found that GALNT12 isnot a major gene modulator in the predisposition to FCCXwhen delineating the relevance of GALNT12mutations in theetiology of FCCX [73] BRCA2 is a putative tumor suppressorgene and plays a pivotal part in repairing DNA Pathogenicmutations in germline DNA are predominantly responsiblefor hereditary breast and ovarian cancer Four BRCA2 vari-ants containing c502CgtA p (Pro168Thr) c927AgtG p (=)c5744CgtT p (Thr1915Met) and c7759CgtT p (Leu2587Phe)show cosegregation with FCCX and may exert a functionas susceptibility alleles in FCCX families [74] A truncatingdominant negative mutation in SETD6 also provides a possi-ble explanation for the cancer predisposition of one FCCXfamily [75] Germline variants in the semaphorin 4A geneincrease the predisposition to colorectal cancers in familieswith FCCX [76] A single truncating germline mutation ofRPS20 a ribosomal protein gene was investigated in fourgenerations of an FCCX family This variant was associatedwith a fault in preribosomal RNA maturation and wasconsidered a new colon cancer predisposition gene [77]

RASL10B encodes a small GTPasewith antitumor proper-ties and epigenetic silencing of this gene has been attributedto hepatocellular carcinoma cells and breast cancer [78 79]RASL10B has been reported to be differentially hypomethy-lated in FXXC cancers compared to Lynch syndrome can-cers [80] RASL10B is one member of Ras superfamilywith antitumor potential Of note segregation of derangedmethylation of RASL10B was revealed in relation to theprogression of sessile serrated adenomaspolyps5 which areregarded as a putative prelude of colon cancer A numberof studies have mainly focused attention on different genesbetween MMR-deficient and MMR-proficient nonpolyposistumors These two groups show various gene expressionprofiles of blood telomere length Many studies support thatlong telomeres are associated with increased cancer risklong telomeres may decrease cell apoptosis accumulatingderanged genomic aberrations FCCX cancer patients hadlonger telomeres than healthy individuals of the same typeX families and LS cancer families [81] MMR-proficientand MMR-deficient tumors show diverse gene expressionprofiles in approximately 2000 significantly different genes

Functional enrichment pathwayswere involved inG-protein-coupled receptor signaling proliferation and migrationcell cycle transition DNA replication and mitosis Severalcandidate target genes such as NDUFA9 AXIN2 MYCand H2AFZ have been specifically linked to FCCX tumors[82]

53 The Histopathologic Features and Clinical Presentation ofFCCX FXXC presents a special clinically different pheno-type compared to that of Lynch syndrome families as follows[83] (1) lower incidence of CRC (2) developing CRC at alater age (3) greater frequency in the distal colon (4) poordifferentiation and more mucinous characteristics (5) dis-tinctive morphological features including tumor-infiltratinglymphocytes and (6) fewer multiple tumors

Obviously FCCX is clearly easily differentiated fromLynch syndrome [84] The identification of differences thatdistinguish patients with FCCX from those with sporadicCRC could reinforce the characteristics of the syndrome butonly the identification of the gene expression associated withFCCX will assist in the early diagnosis of the disease Age atthe diagnosis of cancer is significantly lower in FCCX thanin sporadic CRC Patients with FCCX have an approximatelylarger number of synchronous tumors but this number doesnot reach the level of statistical significance Recurrence isnoticeably higher in FCCX than in sporadic CRC [85] FCCXhas a lower proportion of peritumoral lymphocytes andCrohn-like reactions It is noteworthy that venous invasionis most commonly seen in FCCX [86]

6 Conclusions and Future Perspectives

To our limited knowledge hereditary CRC syndromes are afew causes of CRC in the general population Different cancersyndromes encompass a spectrum of similar clinical presen-tations and genetic profiles These overlapping concepts andtermsmake early diagnosis in hereditary CRC cases clinicallychallenging Therefore an awareness and understanding ofthese unique syndromes may help early diagnosis and pre-ventative interventions in individual patients and their familymembers On the other hand patients with cancer syndromesand their high-risk family members also expect early detec-tion and intense surveillance to prevent and manage severallife-threatening malignancies Moreover screening genetictesting and counseling of at-risk kindred can translate intoa significant benefit across multiple generations demonstrat-ing the tremendous importance of understanding the geneticprofile and clinicopathological features of each syndromeWehave herein provided a comprehensive overview of severalcommon hereditary colorectal nonpolyposis and cancer syn-dromes for clinicians to successfully handle while engagedin a busy clinical practice Physicians should therefore stayabreast of these discoveries

There still remain some problems Interactions withenvironmental factors make the identification and validationof genetic deleterious mutations or genes complicated Firstthe human genome harbors a mass of rare variants most ofwhich may not be clearly or directly associated with diseasephenotypes and second some of these alterations may


interplay with other genetic andor environmental factorswhich may in turn influence their expression

In the era of gene sequencing and other new moleculartechnologies a number of new genesmutations are beingidentified for the prevention and management of many can-cers These new methods will contribute to the investigationof unique genotype-phenotype profiles and may provide thetreatment strategies based on individual risk in precisionmedicine

Conflicts of Interest

The authors disclose no conflicts of interest in this research

Authorsrsquo Contributions

ErbaoChen andXiaojingXu contributed equally to thiswork

Acknowledgments

This research is supported by the National Natural ScienceFoundation of China (81772511 and 81502003)

References

[1] M M Center A Jemal R A Smith and E Ward ldquoWorldwidevariations in colorectal cancerrdquo CA A Cancer Journal forClinicians vol 59 no 6 pp 366ndash378 2009

[2] F M Giardiello J D Brensinger and G M Petersen ldquoAGAtechnical review on hereditary colorectal cancer and genetictestingrdquo Gastroenterology vol 121 no 1 pp 198ndash213 2001

[3] L Aaltonen L Johns H Jarvinen J-P Mecklin and RHoulston ldquoExplaining the familial colorectal cancer risk asso-ciated withmismatch repair (MMR)-deficient andMMR-stabletumorsrdquo Clinical Cancer Research vol 13 no 1 pp 356ndash3612007

[4] P Lichtenstein N V Holm P K Verkasalo et al ldquoEnvironmen-tal and heritable factors in the causation of cancer analyses ofcohorts of twins fromSwedenDenmark and FinlandrdquoTheNewEngland Journal of Medicine vol 343 no 2 pp 78ndash85 2000

[5] L A A Brosens G J A Offerhaus and F M GiardielloldquoHereditary colorectal cancer genetics and screeningrdquo SurgicalClinics of North America vol 95 no 5 pp 1067ndash1080 2015

[6] H T Lynch A J Krush and A L Larsen ldquoHeredity andmultiple primary malignant neoplasms six cancer familiesrdquoThe American Journal of the Medical Sciences vol 254 no 3pp 322ndash329 1967

[7] H F A Vasen J-P Mecklin P M Khan and H T Lynch ldquoTheinternational collaborative group on hereditary non-polyposiscolorectal cancer (ICG-HNPCC)rdquo Diseases of the Colon ampRectum vol 34 no 5 pp 424-425 1991

[8] J T Wijnen H F A Vasen P M Khan et al ldquoClinical findingswith implications for genetic testing in families with clusteringof colorectal cancerrdquoThe New England Journal of Medicine vol339 no 8 pp 511ndash518 1998

[9] H F A Vasen P Watson J-P Mecklin and H T Lynch ldquoNewclinical criteria for hereditary nonpolyposis colorectal cancer(HNPCC Lynch syndrome) proposed by the InternationalCollaborativeGroup onHNPCCrdquoGastroenterology vol 116 no6 pp 1453ndash1456 1999

[10] R W Burt M F Leppert M L Slattery et al ldquoGenetic testingand phenotype in a large kindred with attenuated familialadenomatous polyposisrdquo Gastroenterology vol 127 no 2 pp444ndash451 2004

[11] J Wijnen P Meera Khan H Vasen et al ldquoHereditary nonpoly-posis colorectal cancer families not complying with the Amster-dam criteria show extremely low frequency ofmismatch-repair-gene mutationsrdquo American Journal of Human Genetics vol 61no 2 pp 329ndash335 1997

[12] H Hampel J A Stephens E Pukkala et al ldquoCancer risk inhereditary nonpolyposis colorectal cancer syndrome later ageof onsetrdquo Gastroenterology vol 129 no 2 pp 415ndash421 2005

[13] A Umar C R Boland J P Terdiman et al ldquoRevised bethesdaguidelines for hereditary nonpolyposis colorectal cancer (Lynchsyndrome) andmicrosatellite instabilityrdquo Journal of theNationalCancer Institute vol 96 pp 261ndash268 2004

[14] W Sjursen B I Haukanes E M Grindedal et al ldquoCurrentclinical criteria for Lynch syndrome are not sensitive enough toidentify MSH6 mutation carriersrdquo Journal of Medical Geneticsvol 47 no 9 pp 579ndash585 2010

[15] S M Teutsch L A Bradley G E Palomaki et al ldquoTheevaluation of genomic applications in practice and prevention(EGAPP) initiative methods of the EGAPP working grouprdquoGenetics in Medicine vol 11 no 1 pp 3ndash14 2009

[16] C R Boland and M Shike ldquoReport from the Jerusalem work-shop on Lynch syndrome-hereditary nonpolyposis colorectalcancerrdquo Gastroenterology vol 138 no 7 pp 2197e1ndash2197e72010

[17] J Moline H Mahdi B Yang et al ldquoImplementation of tumortesting for lynch syndrome in endometrial cancers at a largeacademic medical centerrdquo Gynecologic Oncology vol 130 no 1pp 121ndash126 2013

[18] L Moreira F Balaguer N Lindor et al ldquoIdentification of Lynchsyndrome among patients with colorectal cancerrdquo Journal of theAmerican Medical Association vol 308 no 15 pp 1555ndash15652012

[19] Y-E Chen S-S Kao and R-H Chung ldquoCost-effectivenessanalysis of different genetic testing strategies for Lynch syn-drome in Taiwanrdquo PLoS ONE vol 11 no 8 Article ID e01605992016

[20] F Severin B Stollenwerk E Holinski-Feder et al ldquoEconomicevaluation of genetic screening for Lynch syndrome in Ger-manyrdquo Genetics in Medicine vol 17 no 10 pp 765ndash773 2015

[21] H F A Vasen and C R Boland ldquoProgress in genetic testingclassification and identification of lynch syndromerdquo Journal ofthe American Medical Association vol 293 no 16 pp 2028ndash2030 2005

[22] H T Lynch C L Snyder T G Shaw C D Heinen and MP Hitchins ldquoMilestones of Lynch syndrome 1895-2015rdquo NatureReviews Cancer vol 15 no 3 pp 181ndash194 2015

[23] H Kobayashi S Ohno Y Sasaki andMMatsuura ldquoHereditarybreast and ovarian cancer susceptibility genes (Review)rdquoOncol-ogy Reports vol 30 no 3 pp 1019ndash1029 2013

[24] F Gelsomino M Barbolini A Spallanzani G Pugliese andS Cascinu ldquoThe evolving role of microsatellite instability incolorectal cancer a reviewrdquo Cancer Treatment Reviews vol 51pp 19ndash26 2016

[25] N F C C De Miranda M Van Dinther B E W M VanDen Akker T Van Wezel P Ten Dijke and H MorreauldquoTransforming growth factor 120573 signaling in colorectal cancercells with microsatellite instability despite biallelic mutations


in TGFBR2rdquo Gastroenterology vol 148 no 7 pp 1427ndash1437e82015

[26] C D Heinen ldquoMismatch repair defects and Lynch syndromethe role of the basic scientist in the battle against cancerrdquo DNARepair vol 38 pp 127ndash134 2016

[27] Y Jeon D Kim J V Martın-Lopez et al ldquoDynamic controlof strand excision during human DNA mismatch repairrdquoProceedings of the National Acadamy of Sciences of the UnitedStates of America vol 113 no 12 pp 3281ndash3286 2016

[28] V Bonadona B Bonaıti and S Olschwang ldquoCancer risksassociated with germline mutations in MLH1 MSH2 andMSH6 genes in lynch syndromerdquo The Journal of the AmericanMedical Association vol 305 no 22 pp 2304ndash2310 2011

[29] L Senter M Clendenning and K Sotamaa ldquoThe clinical phe-notype of Lynch syndrome due to germ-line PMS2mutationsrdquoGastroenterology vol 135 no 2 pp 419e1ndash428e1 2008

[30] A K Tiwari H K Roy and H T Lynch ldquoLynch syndrome inthe 21st century clinical perspectivesrdquo QJM An InternationalJournal of Medicine vol 109 no 3 pp 151ndash158 2016

[31] B-K Koo M Spit I Jordens et al ldquoTumour suppressorRNF43 is a stem-cell E3 ligase that induces endocytosis of Wntreceptorsrdquo Nature vol 488 no 7413 pp 665ndash669 2012

[32] M Giannakis E Hodis X Jasmine Mu et al ldquoRNF43 isfrequently mutated in colorectal and endometrial cancersrdquoNature Genetics vol 46 no 12 pp 1264ndash1266 2014

[33] L J Fennell M Clendenning D M McKeone et al ldquoRNF43is mutated less frequently in Lynch Syndrome compared withsporadic microsatellite unstable colorectal cancersrdquo FamilialCancer pp 1ndash7 2017

[34] H Binder L Hopp M R Schweiger et al ldquoGenomic andtranscriptomic heterogeneity of colorectal tumours arising inLynch syndromerdquo The Journal of Pathology vol 243 no 2 pp242ndash254 2017

[35] H F A Vasen Z Ghorbanoghli F Bourdeaut et al ldquoGuidelinesfor surveillance of individuals with constitutional mismatchrepair-deficiency proposed by the European Consortium rsquoCarefor CMMR-Drsquo (C4CMMR-D)rdquo Journal of Medical Genetics vol51 no 5 pp 283ndash293 2014

[36] C Maletzki M Huehns I Bauer et al ldquoFrameshift muta-tional target gene analysis identifies similarities and differencesin constitutional mismatch repair-deficiency and Lynch syn-dromerdquo Molecular Carcinogenesis vol 56 no 7 pp 1753ndash17642017

[37] C Palles J B Cazier KMHowarth et al ldquoGermlinemutationsaffecting the proofreading domains of POLE and POLD1predispose to colorectal adenomas and carcinomasrdquo NatureGenetics vol 45 pp 136ndash144 2013

[38] J G Dowty A K Win D D Buchanan et al ldquoCancer risks forMLH1 andMSH2mutation carriersrdquoHumanMutation vol 34no 3 pp 490ndash497 2013

[39] R S C Guindalini A K Win C Gulden et al ldquoMutationspectrum and risk of colorectal cancer in african americanfamilies with lynch syndromerdquo Gastroenterology vol 149 no 6pp 1446ndash1453 2015

[40] C N Ricker D L Hanna C Peng et al ldquoDNAmismatch repairdeficiency and hereditary syndromes in Latino patients withcolorectal cancerrdquo Cancer vol 123 no 19 pp 3732ndash3743 2017

[41] N Chika H Eguchi K Kumamoto et al ldquoPrevalence ofLynch syndrome and Lynch-like syndrome among patientswith colorectal cancer in a Japanese hospital-based populationrdquoJapanese Journal of Clinical Oncology vol 47 pp 108ndash117 2017

[42] T Seppala K PylvanainenDG Evans et al ldquoColorectal cancerincidence in path mlh1 carriers subjected to different follow-up protocols a prospective lynch syndrome database reportrdquoHereditary Cancer in Clinical Practice vol 15 p 18 2017

[43] C R Espenschied H LaDuca S Li R McFarland C-LGau and H Hampel ldquoMultigene panel testing provides a newperspective on Lynch syndromerdquo Journal of Clinical Oncologyvol 35 no 22 pp 2568ndash2575 2017

[44] M W M D Lutgens M G H van Oijen G J M G vander Heijden F P Vleggaar P D Siersema and B OldenburgldquoDeclining risk of colorectal cancer in inflammatory boweldisease an updated meta-analysis of population-based cohortstudiesrdquo Inflammatory Bowel Diseases vol 19 no 4 pp 789ndash799 2013

[45] L A A P Derikx L J T Smits S van Vliet et al ldquoColorectalcancer risk in patients with lynch syndrome and inflammatorybowel diseaserdquoClinical Gastroenterology andHepatology vol 15no 3 pp 454ndash458e1 2017

[46] C Castano-Milla M Chaparro and J P Gisbert ldquoSystematicreview with meta-analysis the declining risk of colorectalcancer in ulcerative colitisrdquo Alimentary Pharmacology ampThera-peutics vol 39 no 7 pp 645ndash659 2014

[47] H F A Vasen I Blanco K Aktan-Collan et al ldquoRevisedguidelines for the clinical management of Lynch syndrome(HNPCC) recommendations by a group of European expertsrdquoGut vol 62 no 6 pp 812ndash823 2013

[48] F M Giardiello J I Allen and J E Axilbund ldquoGuidelineson genetic evaluation and management of lynch syndromea consensus statement by the US multi-society task force oncolorectal cancerrdquo American Journal of Gastroenterology vol109 no 8 pp 1159ndash1179 2014

[49] P Moller T Seppala I Bernstein et al ldquoCancer incidence andsurvival in Lynch syndrome patients receiving colonoscopicand gynaecological surveillance first report from the prospec-tive Lynch syndrome databaserdquo Gut vol 66 pp 464ndash472 2017

[50] P Moslashller T Seppala I Bernstein et al ldquoIncidence of and sur-vival after subsequent cancers in carriers of pathogenic MMRvariants with previous cancer a report from the prospectiveLynch syndrome databaserdquo Gut vol 66 no 9 pp 1657ndash16642017

[51] P Moslashller T T Seppala I Bernstein et al ldquoCancer risk andsurvival in path MMR carriers by gene and gender up to 75years of age a report from the Prospective Lynch SyndromeDatabaserdquo Gut 2017

[52] J M Carethers ldquoDifferentiating lynch-like from lynch syn-dromerdquo Gastroenterology vol 146 no 3 pp 602ndash604 2014

[53] M Rodriguez-Soler L Perez-Carbonell C Guarinos et alldquoRisk of cancer in cases of suspected lynch syndrome with-out germline mutationrdquo Gastroenterology quiz e913ndashe924 pp926e921ndash932e921 2013

[54] J Mas-Moya B Dudley R E Brand et al ldquoClinicopatholog-ical comparison of colorectal and endometrial carcinomas inpatients with Lynch-like syndrome versus patients with Lynchsyndromerdquo Human Pathology vol 46 no 11 pp 1616ndash16252015

[55] L H Katz A M Burton-Chase S Advani et al ldquoScreeningadherence and cancer risk perceptions in colorectal cancersurvivors with Lynch-like syndromerdquo Clinical Genetics vol 89no 3 pp 392ndash398 2016

[56] M Kloth V Ruesseler C Engel et al ldquoActivating ERBB2HER2mutations indicate susceptibility to pan-HER inhibitors in


Lynch and Lynch-like colorectal cancerrdquo Gut vol 65 no 8 pp1296ndash1305 2016

[57] S Traver P Coulombe I Peiffer et al ldquoMCM9 is required formammalian DNA mismatch repairrdquoMolecular Cell vol 59 no5 pp 831ndash839 2015

[58] Q Liu L B Hesson A C Nunez et al ldquoPathogenic germlineMCM9 variants are rare in Australian Lynch-like syndromepatientsrdquo Cancer Genetics vol 209 no 11 pp 497ndash500 2016

[59] D D Buchanan Y Y TanM DWalsh et al ldquoTumormismatchrepair immunohistochemistry and DNA MLH1 methylationtesting of patients with endometrial cancer diagnosed at ageyounger than 60 years optimizes triage for population-levelgermline mismatch repair gene mutation testingrdquo Journal ofClinical Oncology vol 32 no 2 pp 90ndash100 2014

[60] J Rhees M Arnold and C R Boland ldquoInversion of exons 1-7 of the MSH2 gene is a frequent cause of unexplained Lynchsyndrome in one local populationrdquo Familial Cancer vol 13 no2 pp 219ndash225 2014

[61] Q Liu L B Hesson A C Nunez et al ldquoA cryptic paracentricinversion ofMSH2 exons 2-6 causes Lynch syndromerdquoCarcino-genesis vol 37 no 1 pp 10ndash17 2016

[62] S Haraldsdottir H Hampel J Tomsic et al ldquoColon andendometrial cancers with mismatch repair deficiency can arisefrom somatic rather than germline mutationsrdquo Gastroenterol-ogy vol 147 no 6 pp 1308ndash1316e1 2014

[63] S Y Kang C K Park D K Chang et al ldquoLynch-like syndromecharacterization and comparison with EPCAM deletion carri-ersrdquo International Journal of Cancer vol 136 no 7 pp 1568ndash1578 2015

[64] A R Mensenkamp I P Vogelaar W A G van Zelst-Stams etal ldquoSomaticmutations inMLH1 andMSH2 are a frequent causeof mismatch-repair deficiency in lynch syndrome-like tumorsrdquoGastroenterology vol 146 no 3 pp 643ndash646 2014

[65] A P Knopperts M Nielsen R C Niessen et al ldquoContributionof bi-allelic germline MUTYH mutations to early-onset andfamilial colorectal cancer and to low number of adenomatouspolyps case-series and literature reviewrdquo Familial Cancer vol12 no 1 pp 43ndash50 2013

[66] A Castillejo G Vargas M I Castillejo et al ldquoPrevalenceof germline MUTYH mutations among Lynch-like syndromepatientsrdquo European Journal of Cancer vol 50 no 13 pp 2241ndash2250 2014

[67] T Yamaguchi Y Furukawa Y Nakamura et al ldquoComparisonof clinical features between suspected familial colorectal cancertype X and Lynch syndrome in Japanese patients with colorectalcancer a cross-sectional study conducted by the Japanesesociety for cancer of the colon and rectumrdquo Japanese Journalof Clinical Oncology vol 45 no 2 pp 153ndash159 2015

[68] N M Lindor ldquoFamilial colorectal cancer type X the other halfof hereditary nonpolyposis colon cancer syndromerdquo SurgicalOncology Clinics of North America vol 18 no 4 pp 637ndash6452009

[69] C Therkildsen G Jonsson M Dominguez-Valentin et alldquoGain of chromosomal region 20q and loss of 18 discriminatesbetween Lynch syndrome and familial colorectal cancerrdquo Euro-pean Journal of Cancer vol 49 no 6 pp 1226ndash1235 2013

[70] E Sanchez-Tome B Rivera J Perea et al ldquoGenome-wide link-age analysis and tumoral characterization reveal heterogeneityin familial colorectal cancer typeXrdquo Journal of Gastroenterologyvol 50 no 6 pp 657ndash666 2015

[71] S Werdyani Y Yu G Skardasi et al ldquoGermline INDELsand CNVs in a cohort of colorectal cancer patients theircharacteristics associations with relapse-free survival time andpotential time-varying effects on the risk of relapserdquo CancerMedicine vol 6 no 6 pp 1220ndash1232 2017

[72] D R Evans J S Green and M O Woods ldquoScreening ofBMPR1a for pathogenic mutations in familial colorectal cancertype X families from Newfoundlandrdquo Familial Cancer pp 1ndash42017

[73] N Seguı M Pineda M Navarro et al ldquoGALNT12 is not amajor contributor of familial colorectal cancer type Xrdquo HumanMutation vol 35 no 1 pp 50ndash52 2014

[74] P Garre L Martın J Sanz et al ldquoBRCA2 gene a candidatefor clinical testing in familial colorectal cancer type Xrdquo ClinicalGenetics vol 87 no 6 pp 582ndash587 2015

[75] L Martın-Morales M Feldman Z Vershinin P Garre TCaldes and D Levy ldquoSETD6 dominant negative mutation infamilial colorectal cancer type Xrdquo Human Molecular Geneticsvol 26 no 22 pp 4481ndash4493 2017

[76] E Schulz P Klampfl S Holzapfel et al ldquoGermline variants inthe SEMA4A gene predispose to familial colorectal cancer typeXrdquo Nature Communications vol 5 article 6191 2014

[77] T T Nieminen M-F OrsquoDonohue Y Wu et al ldquoGermlinemutation of RPS20 encoding a ribosomal protein causespredisposition to hereditary nonpolyposis colorectal carcinomawithout DNA mismatch repair deficiencyrdquo Gastroenterologyvol 147 no 3 pp 595e5ndash598e5 2014

[78] Z-Y Lin andW-L Chuang ldquoGenes responsible for the charac-teristics of primary cultured invasive phenotype hepatocellularcarcinoma cellsrdquo Biomedicine amp Pharmacotherapy vol 66 no6 pp 454ndash458 2012

[79] H Zou L Hu J Li S Zhan and K Cao ldquoCloning andcharacterization of a novel small monomeric GTPase RasL10Bwith tumor suppressor potentialrdquo Biotechnology Letters vol 28no 23 pp 1901ndash1908 2006

[80] C-H Chen S S Jiang L-L Hsieh et al ldquoDNA methy-lation identifies loci distinguishing hereditary nonpolyposiscolorectal cancer without germ-line MLH1MSH2 mutationfrom sporadic colorectal cancerrdquo Clinical and TranslationalGastroenterology vol 7 no 12 article e208 2016

[81] N Seguı E Guino M Pineda et al ldquoLonger telomeres areassociated with cancer risk in MMR-proficient hereditary non-polyposis colorectal cancerrdquo PLoS ONE vol 9 no 2 Article IDe86063 2014

[82] M Dominguez-Valentin C Therkildsen S Veerla et al ldquoDis-tinct gene expression signatures in lynch syndrome and familialcolorectal cancer type Xrdquo PLoS ONE vol 8 no 8 Article IDe71755 2013

[83] N M Lindor K Rabe G M Petersen et al ldquoLower cancerincidence in Amsterdam-I criteria families without mismatchrepair deficiency familial colorectal cancer type Xrdquo Journal ofthe American Medical Association vol 293 no 16 pp 1979ndash1985 2005

[84] L Valle J Perea P Carbonell et al ldquoClinicopathologic andpedigree differences in Amsterdam I - Positive hereditarynonpolyposis colorectal cancer families according to tumormicrosatellite instability statusrdquo Journal of Clinical Oncologyvol 25 no 7 pp 781ndash786 2007

[85] V Medina-Arana A Rahy-Martın L Delgado-Plasencia etal ldquoClinicopathological differences between familial colorectalcancer type X and sporadic cancer in an isolated area of spainrdquoColorectal Disease vol 18 no 11 pp O388ndashO396 2016


[86] S Shiovitz W K Copeland M N Passarelli et al ldquoCharacteri-sation of familial colorectal cancer type X lynch syndrome andnon-familial colorectal cancerrdquo British Journal of Cancer vol111 no 3 pp 598ndash602 2014

Stem Cells International

Hindawiwwwhindawicom Volume 2018


MEDIATORSINFLAMMATION

of

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Immunology ResearchHindawiwwwhindawicom Volume 2018

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine


Behavioural Neurology

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary andAlternative Medicine

Volume 2018Hindawiwwwhindawicom

Submit your manuscripts atwwwhindawicom


HNPCC clinically determined

MMR-deficient

MMR-proficient

Lynch syndromeGermline mutation+Extracolonic cancers

Lynch-like syndromeGermline mutationminus

Rare extracolonic cancersRelatively younger age

FCCXUnknown genetic causesNo extracolonic cancers

Figure 1 The category of hereditary nonpolyposis colorectal cancer

that modulate growth processes in colonic stem cells andorprotect the fidelity of the genome passed into progeny cellsGiven the substantial risk of synchronous and metachronouscancer these mutation carriers are recommended to abideby standard surveillance and comprehensive managementprotocols when compared with the general population withan average CRC risk profile The role of genetic counselingbecomes crucial in treating these patients

As such understanding and distinguishing the vari-ous syndromes are useful and clinically meaningful as theapproach to diagnosing and surveilling patients and their at-risk family members Previously testing of patient tumorsfor microsatellite instability (MSI) and mutation of DNAMMR genes is an effective strategy to discriminate patientsat risk for Lynch syndrome Cancer-free individuals whosefamily history indicates suspicion for a hereditary cancersyndrome should undertake clinical genetic evaluation andreceive genetic counseling Even if a mutation is not detectedpeople may benefit from the genetic evaluation in otherinterventions to reduce future cancer risk

This paper provides a comprehensive literature reviewon the most common HNPCC and HNPCC-associatedcancer syndromes (including Lynch syndrome Lynch-likesyndrome and familial colorectal cancer type X) that presentdistinguishing molecular phenotypes histopathologic fea-tures and clinical presentations among different subtypes(Figure 1)

2 Diagnosis of Hereditary NonpolyposisColorectal Cancer

The Amsterdam I clinical criteria for HNPCC which focuson the number and ages of family members with colorectalcancer were published in 1990 to standardize the inclusioncriteria for clinical research studies [9] For kindred familiesfulfilling the Amsterdam criteria the chance of identifyinga germline mutation is 40 to 50 [11] Similarly 40 ofpatients with an identified geneticmutation fail tomeet Ams-terdam criteria [12] Therefore Amsterdam I criteria werebelieved to be insufficiently sensitive and to be missing clearfamilial clustering of extracolonic malignancies which led toestablishment of the Amsterdam II criteria in 1999 which

improved the diagnostic sensitivity and included associatedcancers (eg endometrial small bowel) Later Bethesdacriteria were created and revised in 2004 to identify CRCpatients who should undergo pathologic examination (MSIandor immunohistochemistry (IHC) assessment for theMMR protein deficiency in the tumor) for HNPCCLynchsyndrome [13] (Box 1)

Regardless the Amsterdam criteria fail to identifyapproximately 50 of cases and Bethesda guidelines fail toidentify at least 30 of cases [14] which has led to increasedsupport for the universal application of the polymerasechain reaction (for detection of MSI-high tumors) andorIHC testing to all CRC specimens [15] Currently manyguidelines suggest two possible approaches to screen outLynch syndrome a universal one that is to test every patientwith CRC and a selective one (Jerusalem guidelines) whichbroadens the indications for MSI or IHC testing to everyindividual with CRC diagnosed prior to age 70 plus patientsdiagnosed at older ages who meet the Bethesda criteria [16]with the latter approach missing more than a quarter ofpatients with Lynch syndrome (Figure 2) This justificationalso supports the universal testing for endometrial cancer[17] Universal testing followed by germline testing offersthe highest sensitivity (and somewhat lower specificity)than alternative screening strategies although the increasein the diagnostic yield is modest compared with criteria-based screening techniques [18] Cost-effectiveness analysesdemonstrate varying results [19 20] In this review HNPCCgenerally refers to any family that meets the Amsterdam IIIor Revised Bethesda guidelines

3 Lynch Syndrome

31 Overview One of the first hereditary nonpolyposis can-cer-associated syndromes to be identified Lynch syndromeis also the most relevant to HNPCC It is estimated thatLS accounts for approximately 3 of all CRC cases and itsprevalence in the general population is one in 440 [21] Lynchsyndrome also increases the risk for extracolonic cancerssuch as that of the endometrium (50ndash60) ovaries (9ndash14)stomach (13ndash19) small intestine urinary tract and centralnervous system [22 23] (Table 1) Lynch syndrome is now







Positive

Positive

Negative








related tumors




























































Acknowledgments


References
































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of

























Positive

Positive

Negative








related tumors




























































Acknowledgments


References
































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of











































































Acknowledgments


References
































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of

























































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of



















hereditary nonpolyposis colorectal cancer and cancer...

Documents